WO2017020835A1 - 抑制具抗药性微生物的医药组合物及其应用 - Google Patents

抑制具抗药性微生物的医药组合物及其应用 Download PDF

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WO2017020835A1
WO2017020835A1 PCT/CN2016/093065 CN2016093065W WO2017020835A1 WO 2017020835 A1 WO2017020835 A1 WO 2017020835A1 CN 2016093065 W CN2016093065 W CN 2016093065W WO 2017020835 A1 WO2017020835 A1 WO 2017020835A1
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pharmaceutical composition
drug
ala
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opfp
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陈丘泓
陈晔
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肽湛生物科技股份有限公司
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Priority to CN201680045423.2A priority Critical patent/CN107847465B/zh
Priority to EP16832323.6A priority patent/EP3332777A4/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

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  • the present invention relates to a pharmaceutical composition for inhibiting microorganisms having drug resistance and uses thereof.
  • Drug resistance refers to a decrease in the efficacy of a drug to treat a disease or to improve a patient's symptoms.
  • the residual bacteria may have the ability to resist the drug.
  • bacteria may cause resistance to DNA mutations caused by reactive oxygen species produced by antibiotics.
  • the mechanism by which bacteria are resistant to antibiotics is basically controlled by genes, collectively referred to as drug resistance genes. Some of these drug resistance genes are inherently found by certain bacteria, or may be obtained from other bacteria via a plasmid or a transposon. In an environment with antibiotics, it is natural to eliminate the bacteria that can kill the bacteria, leaving only the bacteria with the resistance gene, so in the environment with antibiotics, more and more antibiotics will be derived. Medicinal bacteria. This is the main reason why the more antibiotics are used, the higher the proportion of resistant bacteria.
  • Ampicillin as the first line of antibiotics in clinical medicine, is used for the normal use of medical institutions and the livestock industry, and as a result of the abuse of antibiotics, more and more drug-resistant bacteria appear.
  • 71% of outpatients in Taiwan have resistance to ampicillin in the outpatients, compared with 39.3% in the United States. This condition occurs not only in the first-line antibiotics, but also in the use of vancomycin, which is also used in the treatment of most antibiotics. It also produces resistant bacteria such as vancomycin. Enterococci (Vancomycin-Resistant Enterococcus, VRE).
  • the pharmaceutical company used a relatively simple research and development method to modify only the structure of existing antibiotics, for example, to replace functional groups, but after a few hours of use, the resistant bacteria can still produce modified antibiotics.
  • the new drug resistance if there is no new antibiotics, will not have antibiotics that can effectively treat bacteria and cause the diagnosis of bacterial infections to be incurable.
  • the present invention discloses an antibiotic which can inhibit a microorganism resistant, and the antibiotic is Fmoc-Ala-OPfp.
  • the pharmaceutical composition for inhibiting the growth of microorganisms of the present invention is an antibiotic, N-(9-fluorenylmethoxycarbonyl)-L-alanine pentafluorophenyl, ie Fmoc-Ala-OPfp , CAS: 86060-86-8), the pharmaceutical composition is an alanine (Ala) derivative, and its structural formula is as shown in Formula I.
  • the aforementioned drug-resistant microorganism is selected from the group consisting of Gram-positive bacteria, Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus Pneumoniae, Enterococci, Clostridium tetani botulinum One or more of the genus Clostridium botulinum.
  • the aforementioned drug-resistant microorganism is Staphylococcus aureus.
  • the pharmaceutical composition i.e., antibiotic
  • the pharmaceutical composition has an effective concentration of from 2.5 to 100 uM.
  • the pharmaceutical composition i.e., antibiotic
  • the pharmaceutical composition has an effective concentration of 2.5 uM.
  • the aforementioned drug resistance is tolerant to vancomycin drugs.
  • the present invention further provides a pharmaceutical composition which inhibits the growth of microorganisms, the pharmaceutical composition comprising Fmoc-Ala-OPfp.
  • the invention further provides for the use of a pharmaceutical composition for inhibiting the growth of microorganisms comprising Fmoc-Ala-OPfp.
  • Figure 1 is a hemolytic test of the pharmaceutical composition Fmoc-Ala-OPfp of the present invention.
  • Figure 2 is a toxicity test of human cells of the pharmaceutical composition Fmoc-Ala-OPfp of the present invention.
  • Fig. 3 is a graph showing the comparison of the inhibitory effects of the pharmaceutical composition Fmoc-Ala-OPfp of the present invention against the antibiotic-resistant Staphylococcus aureus of the broad-spectrum antibiotics ampicillin and vancomycin.
  • the present invention carries out a bacterial culture test, and a specific concentration of the pharmaceutical composition of the present invention Fmoc-Ala-OPfp, ampicillin, vancomycin is added to the culture medium as an experimental group, and another medium is not added.
  • Fig. 1 fresh human red blood cells are washed three times with 0.9% physiological saline and then dissolved in physiological saline at a concentration of 2% (V/V), 50 ⁇ L of red blood cell suspension and 50 ⁇ L of the medicine of the present invention.
  • the compositions (10, 50 and 100 ⁇ g/ml antibiotic Fmoc-Ala-OPfp) and Triton X-100 were added to a 96-plate dish with a final concentration of red blood cells of 2% (V/V). The cells were incubated for 1 hour at 37 ° C with gentle shaking in an incubator, and the samples were centrifuged at 2000 g for 30 minutes.
  • Phosphate buffer solution (PBS) physiological saline and Triton X-100 are negative control group and positive control, respectively. group.
  • L292 and MEF cell lines were mammalian cell lines and cultured in Dulbecco's modified Eagle medium (DMEM medium), in which 100 ⁇ g/mL streptomycin (streptomycin) and 100 U/mL penicillin (penicillin) were added to the culture medium. And 10% (v/v) fetal bovine serum (fetal calf serum), which was then cultured in a humidified incubator containing 5% CO 2 and a temperature of 37 °C.
  • DMEM medium Dulbecco's modified Eagle medium
  • streptomycin streptomycin
  • penicillin penicillin
  • the antibiotic Fmoc-Ala-OPfp of the present invention has extremely low cytotoxicity against mammalian cell lines.
  • the toxicity of the compound to mammalian cells was tested by MTT assay, and the cells were cultured in a 96-plate dish after sterilization and cultured in 100 ⁇ L of the culture solution for 24 hours, followed by dilution of the compound in the culture solution, and incubation was continued for 24 hours.
  • the 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazolium bromide (MTT) solution was then added to each of the 96-well plates and incubated for 4 hours.
  • the suspension was removed and 100 ⁇ L of dimethyl sulfoxide (DMSO, dimethyl sulfoxide) was added to dissolve all the precipitate.
  • DMSO dimethyl sulfoxide

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  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
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  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)

Abstract

一种抑制具抗药性微生物的抗生素，所述抗生素为Fmoc-Ala-OPfp，其对人体细胞不具毒性且同时具有能有效抑制具抗药性微生物的功效。

Description

抑制具抗药性微生物的医药组合物及其应用 技术领域
本发明是有关于一种抑制具有抗药性的微生物的医药组合物及其应用。
背景技术
抗药性(drug resistance)是指药物的治疗疾病或改善病人征状的效力降低。当投入药物浓度不足而不能杀死或抑制病原时，残留的细菌可能具有抵抗此种药物的能力。例如细菌可能因抗生素产生的活性氧诱发DNA突变而造成耐药性。
细菌对抗生素产生抗药性的机制基本上是由基因控制，这些基因统称为抗药性基因。这些抗药性基因中，有些是某些细菌天生就具有的，也可能是经由质体(plasmid)或跳跃子(transposon)传递而从其他细菌得到的。在有抗生素的环境中，自然会将药物可杀死的细菌个体淘汰掉，而只剩下带有抗药性基因的细菌，因此在有抗生素的环境下，就会衍生出越来越多的抗药性细菌。这就是为何抗生素使用越多的地区，抗药性细菌的比例越高的主要原因。
近年来因缺乏治疗感染抗药性细菌的抗生素及医界过度滥用，造成强抗药性的突变种细菌，导致欧美地区每年超过4万名丧生。因此，面对俗称「超级细菌」的抗药性细菌，各国皆着手研发新型抗生素。
安比西林(Ampicillin)作为临床医学第一线抗生素，为医疗院所及畜产业常态性使用，也因此抗生素的滥用，出现越来越多具抗药性的细菌。其中，台湾已有71％门诊患者体内大肠杆菌对于安比西林产生抗药性，而美国则为39.3％。该状况不仅出现在第一线抗生素药物，于大部分抗生素均无效治疗后所使用的万古霉素(Vancomycin)，亦由于抗生素滥用的情况下同样产生了具有抗药性的细菌，如抗万古霉素肠球菌(Vancomycin-Resistant Enterococcus，VRE)。
然而，过去药厂为节省成本，因此使用较为简易的研发方法，仅修饰现有抗生素的结构，例如：置换官能基，但经些许时间使用后具抗药性的细菌仍能对修饰后的抗生素产生新的抗药性，系故若再无新型抗生素，将不具有可有效治疗细菌的抗生素而造成确诊细菌感染的病患无药可救的情况。
发明内容
有鉴于此，本发明揭示了一种抗生素并可抑制具抗药性的微生物，所述抗生素为Fmoc-Ala-OPfp。
本发明所述抑制微生物生长的医药组合物是一种抗生素，芴甲氧羰基-L-丙氨酸五氟苯酯(N-(9-fluorenylmethoxycarbonyl)-L-alanine pentafluorophenyl，即Fmoc-Ala-OPfp，CAS:86060-86-8)，所述医药组合物为一种丙氨酸(alanine，Ala)衍生物，其结构式如式I所示。
Figure PCTCN2016093065-appb-000001
较佳地，前述具抗药性的微生物是选自葛兰氏阳性菌、金黄色葡萄球菌Staphylococcus aureus、表皮葡萄球菌Staphylococcus epidermidis、肺炎链球菌Streptococcus Pneumoniae、肠球菌Enterococci、破伤风梭菌Clostridium tetani肉毒杆菌Clostridium botulinum中的一种或多种。
较佳地，前述具抗药性的微生物为金黄色葡萄球菌Staphylococcus aureus。
较佳地，前述医药组合物(即抗生素)的有效浓度为2.5-100uM。
较佳地，前述医药组合物(即抗生素)的有效浓度为2.5uM。
较佳地，前述抗药性为对万古霉素药物具耐受性。
本发明更近一步提供一种可抑制微生物生长的医药组合物，所述医药组合物包含Fmoc-Ala-OPfp。
本发明更近一步提供一种抑制微生物生长的医药组合物的应用，所述医药组合物包含Fmoc-Ala-OPfp。
附图说明
图1为本发明医药组合物Fmoc-Ala-OPfp的溶血性测试。
图2为本发明医药组合物Fmoc-Ala-OPfp的人类细胞的毒性测试。
图3为本发明医药组合物Fmoc-Ala-OPfp与广效性抗生素安比西林、万古霉素的抑制抗药性的黄金葡萄球菌的抑制效果比较图。
具体实施方式
实施例1.抗菌性测试
参见图3，本发明进行细菌培养试验，分别于培养基中加入特定浓度的本发明医药组合物Fmoc-Ala-OPfp、安比西林、万古霉素作为实验组，以及再另一培养基中不添加任何药剂作为控制组，并接种相同菌量的金黄色葡萄球菌后于37℃培养箱中培养；经由测定不同时间点的菌液浓度(OD630)以了解Fmoc-Ala-OPfp、安比西林、万古霉素的抑菌效果。
其中，在培养基中仅添加少量的Fmoc-Ala-OPfp(1μg/ml)，即使在接种细菌8小时后，仍可有效发挥等同于5.3μg/ml的安比西林及5.3μg/ml万古霉素的的抗菌效果，证明Fmoc-Ala-OPfp能有效抑制细菌的生长。
实施例2.溶血性测试
参见图1，新鲜人类红血球细胞由0.9％的生理食盐水冲洗3次后以2％(V/V)的浓度回溶于生理食盐水之中，将50μL的红血球悬浮液及50μL的本发明医药组合物(10、50及100μg/ml抗生素Fmoc-Ala-OPfp)和Triton X-100加入96格盘，其中红血球最后的浓度为2％(V/V)。于培养箱中于37℃并辅以轻微摇动的条件下培养1小时，样本以2000g离心30分钟。取50μL样本的悬浮液并滴入新的96格盘并以O.D.值490nm测量其吸光值(OD490)，磷酸缓冲溶液(PBS)生理食盐水及Triton X-100分别为阴性控制组及阳性控制组。
实施例3.细胞培养
参见图2，L292及MEF细胞株为哺乳类动细胞株并于Dulbecco's modified Eagle培养液(DMEM培养基)中培养，其中培养液加入100μg/mL streptomycin(链霉素)、100U/mL penicillin(青霉素)以及10％(v/v)fetal bovine serum(胎牛血清)，接着将细胞株培于含有5％CO2且温度为37℃的潮湿培养箱中。
如图2所示，本发明抗生素Fmoc-Ala-OPfp对哺乳类动细胞株具有极低之细胞毒性。
实施例4.存活率分析
通过MTT分析法测试化合物对哺乳类细胞所造成的毒性，将细胞培养于灭菌后的96格盘并以100μL培养液培养24小时，接着化合物稀释于培养液之中，并继续培养24小时。之后将3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazolium bromide(MTT)溶液加入96格盘的每一格并培养4小时。移除悬浮液并加入100μL dimethyl sulfoxide(DMSO，二甲亚砜)溶解所有沉淀物。使用酵素免疫分析测读仪以570nm测量吸光值。
如图2、3所示，因此，人类红血球的溶血性实验及MTT分析测试Fmoc-Ala-OPfp的毒性，于100μg/mL的浓度下Fmoc-Ala-OPfp仍具有低溶血性，而于MTT分析中100μg/mL的浓度下Fmoc-Ala-OPfp对细胞仅具有10-20％的毒性。
上列详细说明系针对本发明之一可行实施例的具体说明，惟该实施例并非用以限制本发明的专利范围，凡未脱离本发明技艺精神所为的等 效实施或变更，均应包含于本发明的专利范围中。

Claims (9)

  1. 一种抑制微生物生长的医药组合物，其特征是，所述医药组合物是包含N-(9-fluorenylmethoxycarbonyl)-L-alanine pentafluorophenyl(Fmoc-Ala-OPfp)，其中N-(9-fluorenylmethoxycarbonyl)-L-alanine pentafluorophenyl的结构式如式I所示:
    Figure PCTCN2016093065-appb-100001
  2. 如权利要求1所述的医药组合物，其特征是，所述微生物为具抗药性的微生物。
  3. 如权利要求2所述的医药组合物，其特征是，所述具抗药性的微生物是选自葛兰氏阳性菌、金黄色葡萄球菌(Staphylococcus aureus)、表皮葡萄球菌(Staphylococcus epidermidis)、肺炎链球菌(Streptococcus Pneumoniae)、肠球菌(Enterococci)、破伤风梭菌(Clostridium tetani)、肉毒杆菌(Clostridium botulinum)中的一种或多种。
  4. 如权利要求2所述的医药组合物，其特征是，所述具抗药性的微生物为金黄色葡萄球菌(Staphylococcus aureus)。
  5. 如权利要求1所述的医药组合物，其特征是，所述N-(9-fluorenylmethoxycarbonyl)-L-alanine pentafluorophenyl的有效浓度为2.5-100uM。
  6. 如权利要求1所述的医药组合物，其特征是，所述N-(9-fluorenylmethoxycarbonyl)-L-alanine pentafluorophenyl的有效浓度为2.5uM。
  7. 如权利要求2所述的医药组合物，其特征是，所述抗药性为对万古霉素药物具耐受性。
  8. 一种抑制微生物生长的医药组合物的应用，其特征是，所述医药组合物包含Fmoc-Ala-OPfp。
  9. 如权利要求8项所述之医药组合物，其特征是，所述微生物系为一抗药性之微生物。
PCT/CN2016/093065 2015-08-03 2016-08-03 抑制具抗药性微生物的医药组合物及其应用 WO2017020835A1 (zh)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6482921B1 (en) * 1999-01-28 2002-11-19 Essential Therapeutics, Inc. Uridyl peptide antibiotic (UPA) derivatives, their synthesis and use

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6482921B1 (en) * 1999-01-28 2002-11-19 Essential Therapeutics, Inc. Uridyl peptide antibiotic (UPA) derivatives, their synthesis and use

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
BOOJAMRA C. G. ET AL.: "Stereochemical elucidation and total synthesis of dihydropacidamycin D, a semisynthetic pacidamycin", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 123, no. 5, 1 November 2001 (2001-11-01), pages 870 - 874, XP055362373 *
KISFALUDY L. ET AL.: "Preparation and application of pentafluorophenyl esters of 9-fluorenylmethyloxycarbonyl amino acids for peptide synthesis", SYNTHESIS, 30 April 1983 (1983-04-30), pages 325 - 327, XP055362368 *
SCHON I. ET AL.: "9-Fluorenylmethyl pentafluorophenyl carbonate as a useful reagent for the preparation of N[(9-fluorenylmethoxy) carbonyl] amino acids and their pentafluorophenyl esters", SYNTHESIS, 30 April 1986 (1986-04-30), pages 303 - 305, XP002182716 *
See also references of EP3332777A4 *

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CN107847465B (zh) 2020-10-09
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